Insulin and glucagon are potent regulators of glucose metabolism. For decades, we have viewed diabetes from a bi-hormonal perspective of glucose regulation. This perspective is incomplete and inadequate in explaining some of the difficulties that patients and practitioners face when attempting to tightly control blood glucose concentrations. Intensively managing diabetes with insulin is fraught with frustration and risk. Despite our best efforts,glucose fluctuations are unpredictable, and hypoglycemia and weight gain are common. These challenges may be a result of deficiencies or abnormalities in other glucoregulatory hormones. New understanding of the roles of other pancreatic and incretin hormones has led to a multi-hormonal view of glucose homeostasis.

The objective of this study was to assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in subjects with type 2 diabetes. This 52-week, randomized, placebo-controlled, multicenter, double-blind, dose-ranging study in 538 insulin-treated subjects with type 2 diabetes compared the efficacy and safety of 30-, 75-, or 150-microg doses of pramlintide, a synthetic analogue of the beta-cell hormone amylin, to placebo when injected subcutaneously three times daily (TID) with major meals. Pramlintide therapy led to a mean reduction in HbA1c of 0.9% and 1.0% from baseline to week 13 in the 75- and 150-microg dose groups, which was significant compared to placebo (p = 0.0004 and p = 0.0002, respectively). In the 150-microg dose group, there was a mean reduction in HbA1c of 0.6% from baseline to week 52 (p = 0.0068 compared to placebo). The greater reduction in HbA1c with pramlintide was achieved without increases in insulin use or severe hypoglycemia, and was accompanied by a significant (p < 0.05) reduction in body weight in all dose groups compared to placebo. Three times the proportion of subjects in the 150-microg pramlintide group compared to the placebo group achieved a concomitant reduction in both HbA1c and body weight from baseline to week 52 (48% versus 16%). The most common adverse event reported with pramlintide treatment was nausea, which was mild to moderate and dissipated early in treatment. The results from this study support the safety and efficacy of pramlintide administered three times a day with major meals, in conjunction with insulin therapy, for improving long-term glycemic and weight control in subjects with type 2 diabetes.

OBJECTIVE -To assess the effects of adjunctive treatment with pramlintide, an analog of the ␤-cell hormone amylin, on 24-h glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with continuous subcutaneous insulin infusion (CSII).RESEARCH DESIGN AND METHODS -In this study, 18 patients (16 of whom could be evaluated) with type 1 diabetes (age 44 Ϯ 11 years, HbA 1c 8.2 Ϯ 1.3% [mean Ϯ SD]) were given mealtime injections of 30 g pramlintide t.i.d. for 4 weeks in addition to their preexisting CSII regimen (16 lispro, 2 regular insulin). Mealtime insulin boluses were reduced by a minimum of 10% during the first 3 days, and re-adjusted thereafter based on clinical judgment. At weeks 0 (baseline), 4 (on treatment), and 6 (2 weeks off treatment), 24-h interstitial glucose concentrations were measured using a continuous glucose monitoring system (CGMS), and postprandial plasma glucose, glucagon, and triglyceride concentrations were measured in response to a standardized test meal. RESULTS -At baseline, patients had excessive 24-h glucose fluctuations, with 59% of the CGMS measurements Ͼ140 mg/dl, 13% Ͻ80 mg/dl, and only 28% in the euglycemic range (80 -140 mg/dl). After 4 weeks on pramlintide, measurements in the hyperglycemic range declined to 48% and measurements within the euglycemic range increased to 37%. This shift from the hyperglycemic to the euglycemic range occurred with a concomitant 17% reduction in mealtime insulin dosages and without relevant increases in measurements below the euglycemic range (15%) or any severe hypoglycemic events. After 4 weeks on pramlintide, postprandial glucose, glucagon, and triglyceride excursions were reduced by ϳ86, ϳ87, and ϳ72%, respectively (incremental areas under the curve, all P Ͻ 0.05 vs. baseline). At week 6 (off treatment), the 24-h glucose profile and postprandial glucose, glucagon, and triglyceride excursions approached pretreatment values.CONCLUSIONS -In this study, the addition of pramlintide to insulin therapy reduced excessive 24-h glucose fluctuations as well as postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated benefits for patients with type 2 diabetes including A1C reduction and weight loss with minimal risk of hypoglycemia. This article provides an evidence-based update of safety and tolerability considerations for the clinical use of GLP-1RAs as a class, with a specific detailed review of data from the exenatide clinical trial development program, which has the longest history and availability of safety and tolerability data as the first-approved GLP-1RA. Specific areas covered include comparative risk of hypoglycemia, as well as pancreatic, thyroid, and cardiovascular safety data; clinical guidance regarding current safety and tolerability data is also reviewed.

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